Histone chaperone CAF-1: essential roles in multi-cellular organism development

Abstract

More and more studies have shown chromatin remodelers and histone modifiers play essential roles in regulating developmental patterns by organizing specific chromosomal architecture to establish programmed transcriptional profiles, with implications that histone chaperones execute a coordinating role in these processes. Chromatin assembly factor-1 (CAF-1), an evolutionarily conserved three-subunit protein complex, was identified as a histone chaperone coupled with DNA replication and repair in cultured mammalian cells and yeasts. Interestingly, recent findings indicate CAF-1 may have important regulatory roles during development by interacting with specific transcription factors and epigenetic regulators. In this review, we focus on the essential roles of CAF-1 in regulating heterochromatin organization, asymmetric cell division, and specific signal transduction through epigenetic modulations of the chromatin. In the end, we aim at providing a current image of facets of CAF-1 as a histone chaperone to orchestrate cell proliferation and differentiation during multi-cellular organism development.

Fig. 1

Roles of CAF-1 in DNA replication-coupled assembly of euchromatin and heterochromatin. a During euchromatic DNA replication, PCNA is loaded at the fork. Newly synthesized histone H3–H4 dimers, acetylated by specific histone acetyltransferases (HATs), are brought by Asf1 to the nascent DNA site, then transferred onto the CAF-1 complex, forming a H3–H4 tetramer. Together with the H2A–H2B tetramer brought by Nap1, these acetylated H3–H4 tetramers are assembled into nucleosomes, which consist of mixed histones, either parental or newly synthesized. b During de novo heterochromatin formation, K9 residues on histone H3 tails are mono-methylated by SetDB1 of the CAF-1/HP-1/SetDB1 complex. SU(VAR)3–9 is responsible for the di- and tri-methylation of H3K9 (H3K9me2/3) based on mono-methylated H3K9 (H3k9me1)

Fig. 2

Possible roles of CAF-1 in signal transduction governing multi-cellular organism development, a hypothetic model. During development, specific signals, such as the Notch ligand, initiate a signaling cascade from outside of the cell, generating signals that enter the nucleus, e.g., N^ICD, to interact with specific transcription factors (TF), such as Su(H), recruiting CAF-1 to a specific chromatin region. In this context, CAF-1 regulates the local histone modifications (such as acetylation level) likely by interacting with specific histone modifiers such as a histone acetyltransferase (HAT) or a histone deacetylase (HDAC), which consequently result in either turning-on or shutting-down specific target genes, depending on the newly modified histone marks (active or repressive). However, it is unknown whether in this process CAF-1’s function is dependent on its histone chaperone activity